Ecteinascidins is a group of marine alkaloid having antineoplasticity which is isolated from the extracted products from marine tunicate habitat of Caribbean sea by very small amount. Among the ecteinascidins, since Et 743 has a very strong antineoplastic activity, the investigation to put it into practical use as a carcinostatic agent is limited, and the phase II clinical tests are now carried out in ten several countries in Europe and America. It is known that Et 743 has an effect to depress the proliferation of cancer cells by 10 to 100 times more potent than(IC50=0.1−1 nM) Toxol, Camptotesin, Adriamycin or Mitomycin which are currently used carcinostatic agent.
From the back ground mentioned above, various investigations for synthesis were carried out, however, the complete synthesis was only reported by Prof. E. J. Corey of Harvard University in U.S.A. (J. Am. Chem. Soc. 1996, 118, 9202-9203, reference document A).
In the process of synthesis of the total synthesis disclosed in Document A (refer to page 9202), the feature of the process is existing in the point that Et 743 is synthesized from the analogous compound to the compound represented by general formula 1 of the present invention via intermediates 4 and 8. That is, according to said process, C4 site of ring B (regarding indication of ring, and the sites of atoms composing 6-members ring, refer to general formula 1) which composes 6-members ring is formed from the intermediate 4 at the first step. And, since to the atom C4 composing B ring of 6-membered ring H which lacks reactivity is bonded, it becomes necessary to have an oxidation reaction to C4 site on B ring. This oxidation reaction is not effective and is carried out by harsh condition, therefore, the production by industrial scale is difficult and also the yield is not good. Further, since atom N12 site of the synthesized intermediate is substituted by alkyl group which lacks reactivity, in this case substituted by methyl group, it is not suited to the synthesis for various compounds. Although the total synthesis was reported, the supplying source of Et 743 is still depending on the natural sample whose supplying amount is very scarce, therefore, the establishment of the method for a large scale production of Et 743 is desired by accomplishing an effective synthesizing process.
Since, Et 743 is known as a medicine having high antineoplasticity, and phthalascidin induced from the intermediate product at the synthesis of Et 743 displays same activity to Et 743, the establishment of the effective and mild method for synthesis of Et 743 and analogous compound thereof is strongly desired.
Therefore, the subject of the present invention is basically to accomplish the effective method for total synthesis of Et 743, further, to provide not only Et 743 but also analogous compounds.
To dissolve the subject, the present invention tried the retrosynthetic analysis, which promises easy synthesis. And it will be possible to form B ring by ring forming reaction at ortho position of phenol which composes A ring to inner molecular aldehyde in a generated compound by 4-8 reaction. Further, the inventors of the present invention considered that the generated compound by 4-8 reaction will be possible to synthesize based on the polycondensation reaction of general formula 4, and general formula 5 via a compound of general formula 3, the total synthesis of Et 743, which is the aimed compound, by way of the compounds represented by general formulae 5, 4, 3, 2 and 1 and the specific structure of general formulae 1 and 2. And confirmation of the synthetic route enabled providing the analogous compound of Et 743.